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EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion.

We have examined the mechanism and functional significance of hemidesmosome disassembly during normal epithelial cell migration and squamous carcinoma invasion. Our findings indicate that a fraction of EGF receptor (EGF-R) combines with the hemidesmosomal integrin alpha6beta4 in both normal and neoplastic keratinocytes. Activation of the EGF-R causes tyrosine phosphorylation of the beta4 cytoplasmic domain and disruption of hemidesmosomes. The Src family kinase inhibitors PP1 and PP2 prevent tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes without interfering with the activation of EGF-R. Coimmunoprecipitation experiments indicate that Fyn and, to a lesser extent, Yes combine with alpha6beta4. By contrast, Src and Lck do not associate with alpha6beta4 to a significant extent. A dominant negative form of Fyn, but not Src, prevents tyrosine phosphorylation of beta4 and disassembly of hemidesmosomes. These observations suggest that the EGF-R causes disassembly of hemidesmosomes by activating Fyn, which in turn phosphorylates the beta4 cytoplasmic domain. Neoplastic cells expressing dominant negative Fyn display increased hemidesmosomes and migrate poorly in vitro in response to EGF. Furthermore, dominant negative Fyn decreases the ability of squamous carcinoma cells to invade through Matrigel in vitro and to form lung metastases following intravenous injection in nude mice. These results suggest that disruption of hemidesmosomes mediated by Fyn is a prerequisite for normal keratinocyte migration and squamous carcinoma invasion.

Pubmed ID: 11684709 RIS Download

Mesh terms: Animals | Antigens, Surface | Cell Movement | Enzyme Activation | Epithelial Cells | Hemidesmosomes | Humans | Integrin alpha6beta4 | Integrins | Mice | Mice, Nude | Neoplasm Invasiveness | Neoplasm Metastasis | Neoplasms, Experimental | Phosphorylation | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-fyn | Rats | Receptor, Epidermal Growth Factor | Signal Transduction | Tumor Cells, Cultured | src-Family Kinases

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Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA008748
  • Agency: NCI NIH HHS, Id: R01 CA058976
  • Agency: NCI NIH HHS, Id: P30 CA08748
  • Agency: NCI NIH HHS, Id: R01 CA58976

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American Heart Association

The American Heart Association (AHA) publishes medical scientific statements on various cardiovascular disease and stroke topics. AHA volunteer scientists and healthcare professionals write the papers. The statements are supported by scientific studies published in recognized journals and have a rigorous review and approval process. Scientific statements generally include a review of data available on a specific subject, an evaluation on its relationship to overall cardiovascular disease science, and often an American Heart Association position on the basis of that evaluation. The American Heart Association sponsors accredited scientific conferences and professional development seminars to disseminate new and emerging scientific knowledge and stimulate discussion on future research and the application of knowledge. Keywords: Heart, Cardiovascular, Disease, Stroke, Volunteer, Scientist, Healthcare, Development, Knowledge,

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